The primary objectives of this research are: 1) to build ultra-miniature endoscopes with the capability for simultaneous diffuse white-light reflectance imaging and fluorescence imaging, and 2) to demonstrate unique scientific and clinical applications for these instruments. The catheter of the ultra-miniature endoscope will be based on existing fiber bundle and GRIN lens technology, but will require illumination down the central imaging channel. A novel NA-sharing optical design combined with polarization techniques, anti-reflection coatings, spectral confinement, and data processing will be used to overcome the inherent problem of background signal generated from illumination down the fiber bundle. A novel split-pupil concept will be employed in the system to achieve simultaneous multi-modal acquisition of color images and fluorescence images with high sensitivity. The development of the instrumentation is aimed at multiple scientific and clinical applications. One important scientific application is imaging the esophagus of a mouse model of Barrett's esophagus. During the R21 phase, the instrument concepts will be developed, endogenous diffuse reflectance and autofluorescence contrast will be measured in the mouse esophagus to optimize the system design, image contrast enhancement using exogenous contrast agents will be investigated, and the instrument will be used to evaluate in vivo imaging in mouse esophagus. Assuming the milestones are met, the R33 phase will entail building a fully functional multi-modal imaging instrument including catheters with the necessary functionality. A validation study will be carried out in mouse esophagus to demonstrate the scientific utility and efficacy of the instrument for this particular application. Additional studies will be carried with ex-vivo human tissue specimens and animal models to evaluate the feasibility and efficacy of the proposed clinical applications in bronchial and vascular imaging. [unreadable] [unreadable]